Field of the Invention
The present invention relates generally to the fields of nanomedicine, cancer treatment and tumor targeting. More specifically, the present invention relates to a self-assembly single wall nanotube complex functionalized to deliver a molecule to a cell, for example, a cancer cell, in situ.
Description of the Related Art
The rapidly expanding field of nanomedicine has begun to produce clinical successes in the first generation of engineered drug nanoparticles (1-2). Nanomedicine involves the use of synthetic nanoscale particles that aim to take advantage of the size, shape, and charge of materials to improve drug delivery or efficacy. In addition, the intrinsic properties of some nanomaterials result in unique physicochemical properties. Carbon nanotubes have seen widening application in biomedical research (3), in part because of the potential to append a diverse set of ligands, including small molecules (4), peptides (5-6), oligonucleotides (7), radioisotopes (8), monoclonal antibodies (9-10), and other targeting moieties.
The pharmacokinetics and pharmacodynamics of carbon nanotubes appear to depend highly on the chemical approaches used to render them water dispersable and biocompatible (11-12). Functionalization and dispersion imparts stability in aqueous environments and mitigates potential toxic effects (13). An important feature of covalently functionalized single-walled carbon nanotubes that allows their use as drug carriers is their rapid renal clearance via longitudinal renal glomerular filtration despite apparently large molecular weights (14-16). This clearance phenomenon has been termed fibrillar pharmacology and directly contrasts with the pharmacokinetic profiles of globular proteins.
Typically, in systemic targeting of malignancies, drug delivery vehicles such as mAb or nanoparticles are appended with cytotoxic effectors such as a chemotherapeutic small molecule or radioisotopes in a “single-step” process. However, prolonged half-lives of the effector molecules in vivo, especially those unbound or in excess, will increase toxicity. In contrast, a short circulation time of the agent is problematic as it reduces the time in which a high enough concentration can be maintained in the bloodstream to drive tumor penetration and cell binding.
Two step targeting or pre-targeting separates the required, slow, non-toxic tumor-targeting process of the vehicle from the necessary rapid clearance of the cytotoxic agent to achieve the desired pharmacokinetic goals (17). In this approach, a long-circulating tumor selective agent, such as a monoclonal antibody, is first administered and allowed a sufficient circulation time, typically 2-5 days, to accumulate at the tumor and clear the bloodstream. This is followed by a rapidly cleared, i.e., half life of <10 min, second-step agent, armed with the cytotoxic or diagnostic effector, that has a high-affinity interaction with the initial agent. This interaction may involve streptavidin-biotin (18), bispecific antibody-hapten (19), oligonculeotide hybridization (20), or, more recently, covalent ‘click’ chemistry (21). The second agent rapidly equilibrates with the initial agent, while also clearing the bloodstream. This approach allows for improved ratios of the cytotoxic or imaging agent in the tumor to that in the blood and the corresponding ‘area under the curve’ in concentration versus time, and in other off-site tissues. Pretargeting approaches have been previously explored (22-24), but did not include a second step reagent that both delivered a large payload and cleared quickly, enhancing the therapeutic index.
Because the second step in such a strategy requires rapid clearance, this agent is nearly always a small molecule such as a modified biotin, or a lone, short oligonucleotide. However, small molecules limit potency and sensitivity, as they are usually mono-substituted with the therapeutic or imaging agent, respectively. A highly multivalent effector as a second step should allow for amplification of signal, such as a toxin or diagnostic nuclide, multi-functionality, as well as improved binding affinity (25-26). However, such multivalent constructs as a second step are often too large to allow for the rapid clearance time necessary to avoid toxicity. Therefore, a covalently modified single-walled carbon nanotubes may offer the unique advantage of being highly multivalent and multi-functional while maintaining their rapid clearance.
Thus, there is a recognized need in the art for improved methods for multi-step delivery of a diagnostic and/or a therapeutic molecule or compound using single wall nanotube constructs. The prior art is deficient in the lack of self-assembly single wall nanotube systems effective to deliver a diagnostic and/or therapeutic compound via a two step-cell targeting method without prolonged exposure to a cytotoxic agent during targeting of the cell. The present invention fulfills this longstanding need and desire in the art.